Caged Glutamates with π-Extended 1,2-Dihydronaphthalene

Aug 7, 2014 - ACS eBooks; C&EN Global Enterprise .... Department of Chemistry, Graduate School of Science, Hiroshima University (HIRODAI), .... Sukuma...
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Caged Glutamates with π‑Extended 1,2-Dihydronaphthalene Chromophore: Design, Synthesis, Two-Photon Absorption Property, and Photochemical Reactivity Srikanth Boinapally,†,‡ Bo Huang,† Manabu Abe,*,†,‡ Claudine Katan,*,§ Jun Noguchi,‡,∥ Satoshi Watanabe,‡,∥ Haruo Kasai,‡,∥ Bing Xue,‡,⊥ and Takayoshi Kobayashi‡,⊥ †

Department of Chemistry, Graduate School of Science, Hiroshima University (HIRODAI), 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan ‡ JST-CREST, Gobancho 7 K’s Gabancho, Chiyodaku, Tokyo 102-0075, Japan § Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Université Rennes 1, 35042 Rennes, France ∥ Laboratory of Structural Physiology, CDBIM, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan ⊥ Advanced Ultrafast Laser Research Center, The University of Electro-Communications, Chofugaoka 1-5-1, Chofu, Tokyo 182-8585, Japan S Supporting Information *

ABSTRACT: Caging and photochemical uncaging of the excitatory neurotransmitter L-glutamate (glu) offers a potentially valuable tool for understanding the mechanisms of neuronal processes. Designing water-soluble caged glutamates with the appropriate two-photon absorption property is an attractive strategy to achieve this. This paper describes the design, synthesis, and photochemical reactivity of caged glutamates with π-extended 1,2-dihydronaphthalene structures, which possess a two-photon cross-section of ∼120 GM and an excellent buffer solubility (up to 115 mM). High yields up to 99% glutamate were observed in the photolysis of two caged glutamates. Suzuki−Miyaura cross-coupling and Buchwald−Hartwig amination were used as the key reactions to synthesize the caged compounds.

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INTRODUCTION

In the last two decades, several types of caged glutamates such as nitrobenzyl-, 7-aminocoumarinyl-, ruthenium biphenyl-, and carboxymethylnitroindolinyl-caged compounds have been designed and synthesized for physiological studies (Figure 1). Examples (including their reported two-photon uncaging cross sections, σ2Φu)4 include N-nitrophenethyloxycarbonyl (Nocglu),5 carboxynitrobenzyl (CNB-glu),6 bromohydroxycoumarin (Bhc-glu, 1 GM7/740 nm),8 methoxynitroindolinyl (MNI-glu, 0.06 GM/740 nm),9 carboxymethylnitroindolinyl (CDNI-glu, 0.06 GM/720 nm),10 propylmethoxynitrobiphenyl (PMNB-glu, 0.45 GM/800 nm),11 ruthenium bipyridine (RuBi, 0.14 GM/ 800 nm),12 and bisnitropropylstyrylfluorene (BNSF-glu, 5 GM/800 nm).13 Recently, we reported the synthesis and photochemical reactivity of caged glutamates with a π-extended coumarin chromophore (HBC-glu) as a photolabile protecting group.14 Herein, we report the design, synthesis, and TPA properties of caged glutamates 4 and 5 with a rigid stilbene-based

Caged compounds are important reagents in physiological studies, particularly in the field of neuroscience.1 Spatially and temporally controlled uncaging of neurotransmitters upon photolysis enables a better understanding of in vivo neuronal processes. For example, caged glutamates play a crucial role when studying mammalian learning and memory mechanisms.2 In engineering these probes, several well-defined properties of caged compounds must be considered. A fast and efficient uncaging of the biologically active molecule is important under irradiation conditions, and thermal stability of caged compounds is required in the physiological environment. However, affording both significant two-photon absorption (TPA) and good water solubility are among the most recent issues for in vivo studies of caged compounds. Using two photon (near-IR) as opposed to one (UV−vis) allows a deeper penetration depth, reduces scattering in biological tissues, and also reduces optical absorption by endogenous chromophores, causing less photodamage.3 Thus, the pertinent molecular design and synthesis of new caged compounds, based on chromophores with a high TPA cross-section (σ2 in GM), remains a challenge. © 2014 American Chemical Society

Received: June 26, 2014 Published: August 7, 2014 7822

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Figure 1. Examples of caged glutamates.

computed TPA spectrum of 3, with a sizable TPA cross-section (σ2) from 600 to 900 nm, prompted us to synthesize the caged glutamates 4 and 5, and investigate their photochemical reactivity (Figure 3). Synthesis of Caged Glutamates 4 and 5. Fundamentally, compounds 4 and 5 consisted of three units, which included the photolabile protecting group unit (Unit-1) with an o-nitrophenyl structure and rigid stilbene TPA chromophore; amino groups (Unit-2) with hydrophilic groups, which were an indispensable water solubility unit; and the neurotransmitter glutamic acid (Unit-3). The strategy for the syntheses of caged glutamates 4 and 5 with a rigid stilbene structure is summarized in Figure 3. Caged compounds 4 and 5 were synthesized from a common intermediate 6 by base-mediated bis N-alkylation and the introduction of a glutamate moiety by condensation with the hydroxy terminal. It was anticipated that a Suzuki−Miyaura cross-coupling of enolic triflate 7 with aryl boronate 8 would allow the preparation of the key intermediate 6. Fragments 7 and 8 were obtained from the known 4-bromo-2-tetralone (9) and the commercially available 3-bromobenzaldehyde (10), respectively. The enolic triflate fragment 7 was synthesized in four steps, starting with 4-bromo-2-tetralone 918 (Scheme 1). Ketone protection using ethylene glycol in the presence of catalytic ptoluenesulfonic acid (p-TSA) monohydrate afforded 11 in a 95% yield. The Buchwald amination reaction with tert-butyl carbamate provided 12 in a 85% yield.19 Deprotection of the ethylene ketal moiety was achieved by catalytic usage of p-TSA to furnish 13 in a 80% yield. Ketone 13 was finally converted to the desired enolic triflate 7 using phenyl trifluoromethane sulfonamide (PhNTf2) in a 75% yield. Another fragment, aryl boronate 8, was synthesized from commercially available 3-bromo benzaldehyde (Scheme 2). The aldehyde 10 was subjected to nitration to provide 14 in a 70% yield, followed by rapid reduction with NaBH4 to furnish the primary alcohol 15 in a quantitative yield. The primary alcohol was protected using tert-butyl dimethylsilyl chloride (TBS-Cl) and imidazole to produce silyl ether 16 in a 90% yield. Compound 16 was converted to boronate 8 in a 90% yield using bis(neopentyl glycolato)diboron. With both enolic triflate 7 and aryl boronate 8 fragments, we coupled the fragments to generate the key intermediate 6

structure (see Figure 3). Their photochemical release of glutamate was assessed in this study.

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RESULTS AND DISCUSSION Molecular Design of High TPA Chromophore with Uncaging Reactivity. Extended π-conjugated molecules, such as stilbene derivatives, are promising candidates for chromophores with high TPA responses.15,16 According to the literature, E-stilbene 1 has a TPA cross-section of 12 GM at 514 nm.17 The corresponding computed value at the INDOMRD-CI level at 27.3 GM at 466 nm has the same order of magnitude.16 The major reactivity of the electronically excited state of stilbenes, i.e., the deactivation process, is the cis−trans isomerization reaction. However, the bond-cleavage reaction from the electronically excited state is indispensable for the uncaging of biologically active compounds upon photolysis. Thus, the simple ring-closed 1,2-dihydronaphthalene structures 2 and 3 were selected to avoid any cis−trans isomerization in the electronically excited state. The nitro group is needed for the uncaging process and the amino group for water solubility. This also adds a push−pull character to the chromophores that is well-known to favor increased TPA responses.3k

Initially, the one-photon absorption (OPA) and TPA spectra of parent chromophore units 2 and 3, with a 1,2dihydronaphthalene core, were computed at the TD-B3LYP/ 6-31G(d)//HF/6-31G(d) theory level in a vacuum (Figure 2). This level of theory has been shown to provide accurate predictions for structure−TPA relationships.3k Both chromophores led to sizable TPA cross sections (σ2) of ∼150 GM, however, in different spectral regions (Figure 2; and see the Supporting Information for details). In fact, compound 2 had its first TPA maximum at 470 nm, strongly blue-shifted to two times the wavelength of its first OPA maximum (Figure 2a). As expected, due to the push−pull character introduced by the nitro and amino groups, the first TPA maximum of compound 3 was significantly red-shifted relative to compound 2, with a good agreement between OPA and TPA maxima.3k The 7823

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Figure 2. Calculated OPA (dashed lines) and TPA (solid lines) spectra of (a) compound 2 and (b) compound 3 in a vacuum at the TD-B3LYP/631G(d)//HF/6-31G(d) theory level.

Figure 3. Retrosynthesis of caged glutamates 4 and 5 with a rigid stilbene structure.

Scheme 1a

Scheme 2a

a Reagents and conditions: (a) ethylene glycol, p-TSA·H2O, C6H6, reflux, Dean Stark, 6 h, 95%; (b) tert-butyl carbamate, Cs2CO3, Pd2(dba)3, xanthphos, dioxane, 100 °C, 24 h, 85%; (c) p-TSA·H2O, acetone, rt, 3 h, 80%; (d) PhNTf2, NaHMDS, THF, −78 °C, 0.5 h, 75%.

a

Reagents and conditions: (a) KNO3, H2SO4, 0 °C to rt, 1 h, 70%; (b) NaBH4, MeOH, 0 °C to rt, 15 min, quantitative; (c) TBS-Cl, imidazole, CH2Cl2, 0 °C to rt, 12 h, 90%; (d) bis(neopentyl glycolato) diboron, PdCl2(dppf), CH3COOK, CH3CN, 100 °C, 1 h, 90%.

(Scheme 3). Accordingly, subjection of enolic triflate 7 to Suzuki−Miyaura cross-coupling20 with aryl boronate ester 8 afforded the required skeleton of chromophore 17 in a 85% yield. The deprotection of both the silyl and tert-butyloxycarbonyl (Boc) groups was performed using trifluoroacetic acid, resulting in amino alcohol 6 in a 95% yield. At this stage, water-soluble groups, necessary for biological study, were introduced at the nitrogen terminal. First, treatment

of 6 with 1-bromo-2-(2-(2-methoxyethoxy)ethoxy)ethane and α-bromo tert-butylacetate in the presence of an N-ethyldiisopropylamine base in acetonitrile produced the bis-alkylated products 18 and 19 in 75% and 80% yields, respectively. Finally, the protected glutamic acid Pr-glu ((S)-5-tert-butoxy-4(tert-butoxycarbonylamino)-5-oxopentanoic acid,21 22) was introduced to cages 18 and 19 to provide glutamate analogues 7824

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Scheme 3a

The solubility of 4 and 5 in a HEPES buffer at pH 7.4 was 115 and 35 mM, respectively, at room temperature. Both 4 and 5 were thermally stable in a HEPES buffer up to 100 °C. Photochemical Reactivity of Compounds 20 and 21. The photochemical release of protected glutamic acid 22 from compounds 20 and 21 was investigated by the irradiation of samples (around 10 mM in CD3OD) using a YAG laser at 355 nm (∼7 mJ/pulse) (Figures 4 and 5). The photochemical reaction was monitored using 1 H NMR (400 MHz) spectroscopic analysis. As shown in Figures 4 and 5, quantitative uncaging of the glutamate unit 22 was proven by comparing the 1H NMR spectrum (Figures 4c and 5c) with the authentic sample of 22 (Figures 4d and 5d). The chemical yield of compound 22 after 20 h irradiation was >95% for compound 20 and after 24 h irradiation was >99% for compound 21, using Ph3CH as an internal standard in both cases. The quantum yield for the formation of protected glutamic acid 22 from glutamate analogues 20 (ε355 = 5961) and 21 (ε355 = 5740) was ∼0.01 at 355 nm irradiation using Nd:YAG laser (10 Hz, ∼7 mJ, 4−5 ns pulse-width). The photochemical formation of acetophenone (Φ = 0.33) from valerophenone was used as a chemical actinometer reaction.22 Thus, the ε355Φ value was calculated as 59.6 and 57.6 for 20 and 21, respectively. Synthesis of Parent Compound 23 and Its TPA Spectrum. The photochemically stable compound 23 was synthesized to measure the TPA spectrum (Scheme 4). Enolic triflate 7 was coupled with 4-nitrophenylboronic acid through a Suzuki−Miyaura reaction, using Pd(PPh3)4 and Cs2CO3 and cesium carbonate as a base, leading to the parent core skeleton 23 in a 91% yield. The TPA spectrum of the rigid stilbene chromophore 23 (11.7 mM) is shown in Figure 6b, together with the OPA spectrum (Figure 6a) in chloroform. The TPA spectrum was measured by nondegenerated absorption between the 800 nm pump and white light probe beam. A multichannel lock-in amplifier was used for data collection, which provided fine resolution and high signal-to-noise ratio. A TPA value of ∼120 GM was observed at 680 nm.

a Reagents and conditions: (a) 8, PdCl2(dppf), NEt3, THF/H2O (9:1), reflux, 1 h, 85%; (b) TFA, CH2Cl2, 0 °C to rt, 1 h, 95%; (c) 1-bromo2-(2-(2-methoxyethoxy)ethoxy)ethane or bromo tert-butyl acetate, triisopropylamine, NaI, acetonitrile, reflux, 24 h, 75% for 18 or 80% for 19; (d) ((S)-5-tert-butoxy-4-(tert-butoxycarbonylamino)-5-oxopentanoic acid) (22), EDC, DMAP, CH2Cl2, rt, 24 h, 90% for 20 or 80% for 21; (e) TFA, CH2Cl2, rt, 5 h, quantitative.

20 (λmax 443 nm in MeOH, ε 29520 M−1 cm−1) and 21 (λmax 420 nm in MeOH, ε 18377 M−1 cm−1) in 90% and 80% yields, respectively. The deprotection of trifluoroacetic acid provided caged glutamates 4 and 5 as TFA salts in quantitative yields.

Figure 4. (a) 1H NMR (400 MHz) of compound 20 in CD3OD; (b) 1H NMR spectrum (δ 1.4−4.4 ppm) after 10 h irradiation of 20 using YAG laser (355 nm) in CD3OD; (c) 1H NMR spectrum after 20 h irradiation of 20 in CD3OD; (d) 1H NMR spectrum of protected glutamic acid 22 in CD3OD. 7825

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Figure 5. (a) 1H NMR (400 MHz) of compound 21 in CD3OD; (b) 1H NMR spectrum (δ 1.4−4.4 ppm) after 8 h irradiation of 21 using YAG laser (355 nm) in CD3OD; (c) 1H NMR spectrum after 24 h irradiation of 21 in CD3OD; (d) 1H NMR spectrum of protected glutamic acid 22 in CD3OD.

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Scheme 4. Synthesis of Compound 23 for Measuring the TPA Spectrum

EXPERIMENTAL SECTION

Commercially available reagents and solvents for syntheses were reagent grade and used without further purification. 1H and 13C NMR spectra were recorded with an NMR spectrometer. CDCl3 (0.03% TMS) was used as deuterated solvents. Chemical shifts were reported in parts per million (ppm) relative to tetramethylsilane, and the coupling constants (J) was reported in Hertz (Hz). While the HRMS spectra was recorded on a Orbitrap XL instrument using the positive ion mode. The synthetic procedures for new compounds prepared in this study follow. 6′-Bromo-3′,4′-dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalene] (11). 6-Bromo-3,4-dihydronaphthalen-2(1H)-one (9) (4.5 g, 20.1 mmol) was dissolved in benzene (50 mL), to which ethylene glycol (2.27 mL, 40.2 mmol) and p-TSA·H2O (191 mg, 1.0 mmol) were added. The solution was heated under reflux conditions with a Dean−Stark trap attached for 6 h. The reaction mixture was cooled and washed with saturated aq NaHCO3 (20 mL) and water (20 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. Crude was purified by flash silica gel column chromatography (15% ethyl acetate in hexanes) to give required compound 11 (5.2 g, 95%): IR (neat) ν 2951, 2881, 1591, 1484, 1104,

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SUMMARY In summary, this study designed and synthesized two new caged glutamates with π-extended 1,2-dihydronaphthalene chromophore. The synthetic sequence was highly convergent with an overall yield of approximately 28%. These two caged glutamates 4 and 5 showed excellent buffer solubility (up to 115 mM), with the photochemical reaction shown to release glutamic acids in high yields (>95%). A TPA value of ∼120 GM at 680 nm was obtained for the parent structure 23. Further elaboration of this sequence for more efficient caged glutamates is currently underway in our laboratory.

Figure 6. (a) OPA spectra of compound 23, λ 250−550 nm. (b) TPA spectra of compound 23, λ 630−750 nm. 7826

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1062, 859, 803, 701 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.27 (s, 1H), 7.23 (dd, J = 8.5, 2.1 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 4.04− 4.00 (m, 4H), 2.95 (t, J = 6.9 Hz, 2H), 2.92 (s, 2H), 1.93 (t, J = 6.8 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 137.6, 133.4, 131.2, 130.7, 128.8, 119.6, 107.8, 64.5, 38.7, 31.4, 27.8; HRMS-APCI calcd for C12H14O2Br 269.0171, found 269.0172 [M + H]+. tert-Butyl (3′,4′-Dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalen]-6′-yl)carbamate (12). 6′-Bromo-3′,4′-dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalene] (3.7 g, 13.7 mmol), tert-butyl carbamate 11 (1.93 g, 16.5 mmol), cesium carbonate (6.72 g, 20.6 mmol), Pd2(dba)3 (125 mg, 0.13 mmol), and xanthphos (238 mg, 0.41 mmol) in anhydrous dioxane (20 mL) were heated at 100 °C under nitrogen atmosphere for 5 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane (50 mL), filtered, and concentrated in vacuo. The crude was purified by flash silica gel column chromatography (20% ethyl acetate in hexanes) to give the required compound 12 (3.56 g, 85%): mp 144−145 °C; IR (neat) ν 3337, 2977, 1724, 1532, 1366, 1243, 1058, 882, 814 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.20 (s, 1H), 7.02 (dd, J = 7.8, 2.1 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.46 (s, 1H), 4.03−3.99 (m, 4H), 2.94 (t, J = 6.9 Hz, 2H), 2.92 (s, 2H), 1.92 (t, J = 6.7 Hz, 2H), 1.50 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 152.8, 136.3, 135.9, 129.5, 129.1, 118.3, 116.6, 108.3, 80.2, 64.4, 38.5, 31.7, 28.3, 28.1; HRMS-ESI calcd for C17H23O4NNa 328.1519, found 328.1524 [M + Na]+. 6-((tert-Butoxycarbonyl)amino)-3,4-dihydronaphthalen-2-yl Trifluoromethanesulfonate (7). To the stirred solution of tert-butyl (3′,4′-dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalen]-6′-yl)carbamate (12) (3 g, 9.83 mmol) in acetone (30 mL) was added pTSA·H2O (186 mg, 0.97 mmol). Stirring was continued for 3 h at room temperature. After completion of reaction, the reaction mixture was cooled to 0 °C and quenched with saturated aqueous NaHCO3 (10 mL). The reaction mixture was evaporated at reduced pressure, and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, dried over Na2SO4, filtered, evaporated under reduced pressure, and purified through silica gel column chromatography (20% ethyl acetate in hexanes) to give required compound 13 (2 g, 80%). The product was not stable, so it was used immediately in the next step. tert-Butyl (6-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)carbamate (13) (750 mg, 2.87 mmol) and N-phenylbis(trifluoromethanesulfonimide) (1.33 g, 3.7 mmol) were dissolved in anhydrous THF (30 mL), and the mixture was cooled to −78 °C under nitrogen atmosphere. To this solution sodium bis(trimethylsilyl)amide (0.6 M solution in toluene, 9.5 mL, 5.74 mmol) was added dropwise via syringe at −78 °C slowly dropwise (color changes to orange). The mixture was stirred at −78 °C for an additional 30 min (monitored by TLC) before the reaction was quenched by addition of distilled water. The reaction mixture was then extracted with Et2O (3 × 10 mL), washed with brine (20 mL), dried over Na2SO4, and filtered, and the solvent was evaporated in vacuo. Purification by flash silica gel column chromatography (10% ethyl acetate in hexanes) afforded required compound 7 (1.12 g, 75%): mp 80−82 °C; IR (neat) ν 3318, 2995, 1693, 1580, 1522, 1240, 1141, 1061, 886, 755 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.32 (s, 1H), 7.06 (dd, J = 8.2, 2.2 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.50 (s, 1H), 6.42 (s, 1H), 3.02 (t, J = 8.5 Hz, 2H), 2.66 (t, J = 8.5 Hz, 2H), 1.52 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 152.6, 148.7, 138.5, 134.1, 127.8, 125.9, 119.9, 118.1, 117.6, 116.5, 80.8, 28.8, 28.3, 26.4; HRMSESI calcd for C16H18O5NF3NaS 416.0750, found 416.0747 [M + Na]+. (5-Bromo-2-nitrophenyl)methanol (15). To a stirred solution of 5-bromo-2-nitrobenzaldehyde (14) (1 g, 4.38 mmol) in methanol (20 mL) at 0 °C was added sodium borohydride (162 mg, 4.38 mmol) in portions. Stirring was continued for an additional 15 min at room temperature for complete reaction to take place. Methanol was evaporated from the reaction mixture, the reaction was quenched with cold water, and the mixture was extracted with ethyl acetate (3 × 20 mL). Combined organic layers was washed with brine (20 mL), dried over NaSO4, and filtered. The solvent was evaporated under reduced pressure and purified through flash silica gel column chromatography (30% ethyl acetate in hexanes) to give the required product 15 (1.0 g, quantitative): mp 91−92 °C; IR (neat) ν 3252, 1601, 1518, 1346,

1040, 831, 746 cm−1; 1H NMR (500 MHz, CD3OD) δ 7.97 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.56 (dd, J = 1.9, 8.8 Hz, 1H), 4.90 (s, 2H); 13 C NMR (125 MHz, CD3OD) δ 146.8, 141.5, 132.1, 131.7, 129.7, 127.2, 61.3; HRMS-APCI calcd for C7H6O3NBr 230.9525, found 230.9525 [M]+. ((5-Bromo-2-nitrobenzyl)oxy)-tert-butyldimethylsilane (16). To a stirred solution of (5-bromo-2-nitrophenyl)methanol (15) (1 g, 4.3 mmol) in CH2Cl2 (20 mL) at 0 °C was added imidazole (586 mg, 8.62 mmol). After the solution was stirred for 10 min, tertbutyldimethylsilyl chloride (969 mg, 6.46 mmol) was added. The temperature was raised to 25 °C, and stirring was continued for an additional 12 h at room temperature. After completion of reaction, water (20 mL) was added to reaction mixture. The organic layer was separated, washed with brine (20 mL), dried over Na2SO4, and filtered. Solvent was evaporated under reduced pressure and purified through flash silica gel column chromatography (5% ethyl acetate in hexanes) to give the required product 16 (1.35 g, 90%): mp 38−40 °C; IR (neat) ν 2955, 2857, 1604, 1566, 1343, 1109, 837, 779 cm−1; 1 H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 5.08 (s, 2H), 0.98 (s, 9H), 0.16 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 145.1, 140.5, 131.3, 130.6, 129.4, 126.1, 61.8, 25.9, 18.3, −5.4; HRMS-APCI calcd for C13H21O3NBrSi 346.0468, found 346.0472 [M + H]+. tert-Butyl((5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-nitrobenzyl)-oxy)dimethylsilane (8). A mixture of ((5-bromo-2nitrobenzyl)oxy)(tert-butyl)dimethylsilane 16 (1.2 g, 3.47 mmol), potassium acetate (1.02 g, 10.4 mmol), Pd(dppf) Cl2 (142 mg, 0.17 mmol)and bis(neopentyl glycolate)diboron (1.18 g, 5.2 mmol) in acetonitrile (20 mL) was heated at reflux under nitrogen atmosphere for 1 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and filtered with Celite. The filtrate was concentrated under reduced pressure and purified through silica gel column chromatography (10% ethyl acetate in hexanes) to afford required compound 8 (1.18 g, 90%). m.p: 40−41 °C; IR (neat) ν 2958, 2857, 1520, 1479, 1335, 1255, 1130, 838, 778 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.28 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 5.08 (s, 2H), 3.79 (s, 4H), 1.03 (s, 6H), 0.97 (s, 9H), 0.13 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 148.3, 136.3, 133.9, 132.9, 123.3, 62.3, 31.9, 25.9, 21.8, 18.4, −5.4; HRMS-APCI calcd for C18H31O5NBSi: 380.2059, found 380.2065 [M + H]+. tert-Butyl (6-(3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-nitrophenyl)-7,8-dihydronaphthalen-2-yl)carbamate (17). A magnetically stirred solution of 6-((tert-butoxycarbonyl)amino)-3,4-dihydronaphthalen-2-yl trifluoro-methanesulfonate (7) (1 g, 2.54 mmol) in THF/H2O (60 mL) (9:1) was mixed with tert-butyl((5-(5,5-dimethyl1,3,2-dioxaborinan-2-yl)-2-nitrobenzyl)-oxy)dimethylsilane (1 g, 2.63 mmol), triethylamine (3.5 mL, 25.3 mmol), and Pd(dppf)Cl2 (207 mg, 0.25 mmol). The reaction was run under nitrogen atmosphere with refluxing for 1 h. The cooled reaction mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and filtered, and solvent was evaporated under reduced pressure and purified through silica gel column chromatography (10% ethyl acetate in hexanes) to afford target compound 17 (1.1 g, 85%): mp 123−125 °C; IR (neat) ν 3350, 2930, 1730, 1574, 1516, 1332, 1252, 1106, 836, 778 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.14 (d, J = 8.7 Hz, 1H), 8.09−8.06 (m, 1H), 7.52 (dd, J = 8.4, 2.0 Hz, 1H), 7.35 (s, 1H), 7.12−7.06 (m, 2H), 6.99 (s, 1H), 6.53 (s, 1H), 5.15 (s, 2H), 2.96 (t, J = 8.5 Hz, 2H), 2.75 (t, J = 8.5 Hz, 2H), 1.53 (s, 9H), 1.00 (s, 9H), 0.16 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 152.6, 146.8, 144.4, 138.9, 138.1, 136.4, 135.0, 129.2, 127.9, 127.4, 125.2, 123.8, 123.3, 117.4, 116.4, 80.7, 62.3, 28.3, 28.2, 25.9, 25.8, 18.3, −5.4; HRMS-ESI calcd for C28H38O5N2NaSi 533.2442, found 533.2438 [M + Na]+. (5-(6-Amino-3,4-dihydronaphthalen-2-yl)-2-nitrophenyl)methanol (6). To a stirred solution of tert-butyl (6-(3-(((tertbutyldimethylsilyl)oxy)methyl)-4-nitrophenyl)-7,8-dihydronaphthalen-2-yl)carbamate (17) (1 g, 1.96 mmol) in THF (40 mL) was added slowly TFA (10 mL) at 0 °C. Subsequently, the temperature was raised to 25 °C and stirring was continued for an additional 1 h. After completion of the reaction, the reaction mixture was evaporated, 7827

dx.doi.org/10.1021/jo501425p | J. Org. Chem. 2014, 79, 7822−7830

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3445, 2891, 2608, 196, 1784, 1696, 1514, 1333, 1131, 764, 594 cm−1; H NMR (500 MHz, DMSO-d) δ 8.32 (s, 3H), 8.11 (d, J = 8.2 Hz, 1H), 7.77 (s, 1H), 7.74 (dd, J = 8.8, 1.9 Hz, 1H), 7.17 (s, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.59 (s, 1H), 6.54 (dd, J = 8.4, 2.1 Hz, 1H), 5.47 (s, 2H), 3.98 (s, 1H), 3.60−3.46 (m, 20H), 3.41 (t, J = 4.1, 4H), 3.23 (s, 6H), 2.85 (t, J = 8.2, 2H), 2.66 (t, J = 8.2, 2H), 2.71−2.53 (m, 2H), 2.18−2.00 (m, 2H); 13C NMR (125 MHz, DMSO-d) δ 171.33, 147.93, 146.43, 144.67, 136.57, 131.68, 129.53, 128.96, 128.50, 125.59, 125.15, 124.41, 122.03, 110.47, 109.36, 71.24, 69.93, 69.80, 69.61, 67.90, 63.21, 57.99, 50.21, 29.14, 28.18, 27.40, 25.17, 24.94; HRMSESI calcd for C36H52O12N3 718.3546, found 718.3545 [M + H]+. tert-Butyl 2,2′-(6-(3-(Hydroxymethyl)-4-nitrophenyl)-7,8-dihydronaphthalen-2-ylazanediyl)diacetate (19). To an anhydrous acetonitrile (2.0 mL) solution of (5-(6-amino-3,4-dihydronaphthalen2-yl)-2-nitrophenyl)methanol (6 )(25 mg, 0.084 mmol), sodium iodide (126.5 mg, 0.84 mmol), and N-ethyldiisopropylamine (54.6 mg, 0.42 mmol) was added tert-butyl bromoacetate (164 mg, 0.84 mmol). The reaction mixture was heated under reflux for 24 h. After the mixture was cooled to room temperature, solvent was evaporated and diluted with CH2Cl2, and white solids were filtered. Filtrate was concentrated in vacuo and purified through silica gel column chromatography (20% ethyl acetate in hexanes) to afford required compound 19 (35 mg, 80%): IR (neat) ν 2978, 1734, 1597, 1510, 1456, 1330, 1213, 1149, 1085, 842, 622 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 8.8, 2.5 Hz, 1H), 7.75 (d, J = 1.9 Hz, 1H), 7.51 (td, J = 8.5, 2.4 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 6.97 (s, 1H), 6.42− 6.40 (m, 1H), 6.39 (s, 1H), 4.97 (s, 2H), 4.01 (s, 4H), 2.89 (t, J = 8.0 Hz, 2H), 2.64 (t, J = 8.0 Hz, 2H), 1.47 (s, 18 H); 13C NMR (100 MHz, CDCl3) δ 169.9, 148.2, 147.6, 145.0, 137.3, 136.7, 13.7, 128.7, 128.4, 125.7, 125.5, 124.5, 123.9, 111.5, 110.2, 81.9, 63.8, 54.5, 28.8, 28.1, 25.8; HRMS-ESI calcd for C29H36O7N2Na 547.2414, found 547.2409 [M + Na]+. (S)-5-(5-(6-(Bis(2-tert-butoxy-2-oxoethyl)amino)-3,4-dihydronaphthalen-2-yl)-2-nitrobenzyl) 1-tert-Butyl 2-(tertButoxycarbonylamino)pentanedioate (21). To a solution of tert-butyl 2,2′-(6-(3-(hydroxymethyl)-4-nitrophenyl)-7,8-dihydronaphthalen-2-ylazanediyl)diacetate (19) (34 mg, 0.064 mmol) in DCM (2 mL) was added (S)-5-tert-butoxy-4-((tert-butoxycarbonyl)amino)-5oxopentanoic acid (22) (39 mg, 0.129 mmol), EDC (18.6 mg, 0.097 mmol), and DMAP (0.8 mg, 0.0064 mmol). The reaction was allowed to stir for 12 h for complete reaction. The reaction was diluted with CH2Cl2 (5 mL), washed with 1 M HCl, saturated NaHCO3 solution, and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% ethyl acetate in hexanes) to provide required compound 21 (42 mg, 80%): IR (neat) ν 2979, 2930, 1741, 1600, 1577, 1506, 1457, 1333, 1216, 1152, 843, 797 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.11 (dd, J = 8.5 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.6, 2.0 Hz, 1H), 7.05 (d, J = 9.1 Hz, 1H), 6.95 (s, 1H), 6.43−6.41 (m, 1H), 6.40 (s, 1H), 5.54 (s, 1H), 5.09 (d, J = 7.6 Hz, 1H), 4.27−4.17 (m, 1H), 4.03 (s, 4H), 2.90 (t, J = 7.7, 2H), 2.70 (t, J = 7.7 Hz, 6H), 2.60−2.41 (m, 2H), 2.27− 2.15 (m, 1H), 2.01−1.90 (m, 1H), 1.47 (s, 18H), 1.45 (s, 9H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.2, 171.2, 169.9, 155.4, 148.2, 147.3, 145.0, 136.6, 132.2, 131.5, 128.8, 128.4, 125.7, 124.9, 124.4, 124.3, 111.4, 110.2, 82.3, 81.8, 63.6, 54.5, 53.3, 30.2, 28.8, 28.3, 28.1, 27.9, 25.8; HRMS-ESI calcd for C43H59O12N3Na 832.3991, found 832.3994 [M + Na]+. (S)-2,2′-(6-(3-((4-Amino-4-carboxybutanoyloxy)methyl)-4nitrophenyl)-7,8-dihydronaphthalen-2-ylazanediyl)diacetic Acid (5). To a stirred solution of (S)-5-(5-(6-(bis(2-tert-butoxy-2oxoethyl)amino)-3,4-dihydronaphthalen-2-yl)-2-nitrobenzyl) 1-tertbutyl 2-(tert-butoxycarbonylamino)pentanedioate (21) (40 mg, 0.049 mmol) in anhydrous CH2Cl2 (3 mL) was added trifluoroacetic acid (1.0 mL). After 5 h at room temperature under nitrogen atmosphere, the solution was evaporated to yield caged glutamate 5 (32 mg, quantitative yield): IR (neat) ν 3437, 2935, 2633, 1734, 1601, 1510, 1331, 1190, 1139, 1080, 842 cm−1; 1H NMR (400 MHz, DMSO-d) δ 8.24 (s, 3H), 8.05 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 13.0 Hz, 1H), 7.12 (s, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.36 (s, 1H), 6.31 (d, J = 7.7 Hz, 1H), 5.40 (s, 2H), 4.07 (s, 4H), 3.95−3.86 (m, 1H), 2.78 (t, J = 7.7

quenched with saturated aqueous NaHCO3 (10 mL), and extracted with ethyl acetate (3 × 20 mL), the combined organic layers were dried over Na2SO4 and filtered, and solvent was evaporated under reduced pressure and purified through silica gel column chromatography (5% methanol in chloroform) to afford target compound 6 (550 mg, 95%): mp 138−140 °C; IR (KBr): ν 3389, 3276, 2931, 1599, 1497, 1214, 1082, 878, 832, 755 cm−1; 1H NMR (500 MHz, DMSOd6) δ 8.05 (d, J = 8.7 Hz, 1H), 7.95 (s, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.08 (s, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.99 (s, 1H), 6.44−6.38 (m, 2H), 5.56 (t, J = 5.6 Hz, 1H), 5.38 (s, 2H), 4.88 (d, J = 5.5 Hz, 2H), 2.77 (t, J = 8.4 Hz, 2H), 2.63 (t, J = 8.4 Hz, 2H); 13C NMR (125 MHz, DMSO-d6) δ 149.3, 146.4, 143.9, 139.2, 136.4, 129.6, 128.9, 128.4, 128.3, 123.2, 122.9, 122.3, 112.8, 111.6, 60.3, 28.0, 25.1; HRMSESI calcd for C17H16O3N2Na 319.1053, found 319.1057 [M + Na]+. (5-(6-(Bis(2-(2-(2-methoxyethoxy)ethoxy)ethyl)amino)-3,4dihydronaphthalen-2-yl)-2-nitrophenyl)methanol (18). To an anhydrous acetonitrile (8.0 mL) solution of (5-(6-amino-3,4dihydronaphthalen-2-yl)-2-nitrophenyl)methanol (6) (204 mg, 0.68 mmol), sodium iodide (1 g, 6.6 mmol), and N-ethyldiisopropylamine (436 mg, 3.37 mmol) was added 1-bromo-2-(2-(2-methoxyethoxy)ethoxy)ethane (760 mg, 3.34 mmol). The reaction mixture was heated under reflux for 5 days. After the mixture was cooled to room temperature, white solids were filtered. The filtrate was washed with water, dried over Na2SO4, and purified through silica gel column chromatography (100% ethyl acetate) to afford required compound 18 (303 mg, 75%): IR (neat) ν 3435, 2821, 1595, 1511, 1328, 1213, 1086, 1030, 835, 799 cm−1; 1H NMR (500 MHz, CD3CN) δ 8.13 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 8.8, 2.1 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 6.57−6.53 (m, 2H), 5.00 (d, J = 3.3, 2H), 3.69− 3.59 (m, 20H), 3.57−3.53 (m, 4H), 3.38 (s, 6H), 2.92 (t, J = 8.5 Hz, 2H), 2.73 (t, J = 8.5 Hz, 2H); 13C NMR (125 MHz, CD3CN) δ 149.2, 148.0, 145.5, 139.7, 138.0, 129.9, 129.0, 126.2, 124.6, 124.0, 118.3, 111.8, 110.6, 72.6, 71.4, 71.2, 71.1, 69.3, 62.2, 58.9, 51.6, 29.5, 26.5; HRMS-ESI calcd for C31H44O9N2Na 611.2939, found 611.2934 [M + Na]+. (S)-5-(5-(6-(Bis(2-(2-(2-Methoxyethoxy)ethoxy)ethyl)amino)3,4-dihydronaphthalen-2-yl)-2-nitrobenzyl) 1-tert-Butyl 2((tert-butoxycarbonyl)amino)pentanedioate (20). To a solution of (5-(6-(bis(2-(2-(2-methoxyethoxy)ethoxy)ethyl)amino)-3,4-dihydronaphthalen-2-yl)-2-nitrophenyl)methanol (18) (110 mg, 0.18 mmol) in DCM (2 mL) were added (S)-5-tert-butoxy-4-((tertbutoxycarbonyl)amino)-5-oxopentanoic acid (113 mg, 0.37 mmol), EDC (53.8 mg, 0.28 mmol), and DMAP (2.2 mg, 0.018 mmol). The reaction was allowed to stir for 20 h for complete reaction. The reaction was diluted with CH2Cl2 (5 mL), washed with 1 M HCl, saturated NaHCO3 solution, and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (100% ethyl acetate) to provide required compound 20 (147 mg, 90%): IR (neat) ν 3336, 2876, 1738, 1598, 1472, 1393, 1213, 1149, 932, 847, 798 cm−1; 1H NMR (500 MHz, CD3CN) δ 8.08 (dd, J = 8.8, 2.4 Hz, 1H), 7.73 (s, 1H), 7.62 (d, J = 9.1 Hz, 1H), 7.07 (s, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.59 (s, 1H), 6.55 (d, J = 8.5 Hz, 1H), 5.55 (d, J = 7.8 Hz, 1H), 5.47 (s, 2H), 4.07−3.98 (m, 1H), 3.63− 3.52 (m, 20H), 3.45 (t, J = 4.2, 4H), 3.28 (s, 6H), 2.87 (t, J = 8.2, 2H), 2.68 (t, J = 8.2, 2H), 2.50 (t, J = 7.5 Hz, 2H), 2.14−2.04 (m, 1H), 1.93−1.85 (m, 1H), 1.42 (s, 9H), 1.38 (s, 9H); 13C NMR (125 MHz, CD3CN) δ 173.2, 149.4, 148.2, 145.9, 138.0, 133.5, 131.3, 130.0, 129.6, 129.5, 126.6, 125.4, 125.1, 123.5, 118.3, 111.8, 110.6, 82.3, 79.9, 72.6, 73.4, 71.2, 71.1, 69.3, 64.2, 58.9, 51.6, 31.1, 29.5, 28.5, 28.1, 27.8, 26.4; HRMS-ESI calcd for C45H67O14N3Na 896.4515, found 896.4490 [M + Na]+. (S)-2-Amino-5-((5-(6-(bis(2-(2-(2-methoxyethoxy)ethoxy)ethyl)amino)-3,4-dihydronaphthalen-2-yl)-2-nitrobenzyl)oxy)5-oxopentanoic Acid (4). To a stirred solution of (S)-5-(5-(6(bis(2-(2-(2-ethoxyethoxy)ethoxy)ethyl)amino)-3,4-dihydronaphthalen-2-yl)-2-nitrobenzyl) 1-tert-butyl 2-((tert-butoxycarbonyl)amino)pentanedioate 20 (25 mg, 0.028 mmol) in anhydrous CH2Cl2 (1 mL) was added trifluoroacetic acid (0.25 mL). After 5 h at room temperature under nitrogen atmosphere the solution was evaporated to yield caged glutamate 4 (20 mg, quantitative yield): IR (neat) ν

1

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Hz, 2H), 2.60 (t, J = 7.7, 2H), 2.56−2.46 (m, 2H), 2.11−1.89 (m, 2H); 13C NMR (100 MHz, DMSO-d) δ 172.5, 171.8, 171.0, 148.6, 146.7, 145.3, 136.8, 132.2, 130.9, 129.2, 128.7, 126.1, 125.7, 125.0, 123.7, 111.1, 110.0, 63.6, 56.4, 53.3, 29.6, 28.5, 25.6, 25.4; HRMS-ESI calcd for C26H28O10N3 542.1769, found 542.1765 [M + H]+. tert-Butyl (6-(4-Nitrophenyl)-7,8-dihydronaphthalen-2-yl)carbamate (23). 6-((tert-Butoxycarbonyl)amino)-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate 7 (200 mg, 0.5 mmol), 4nitrobenzeneboronic acid (170 mg, 1.0 mmol), cesium carbonate (829 mg, 2.5 mmol), and Pd(PPh3)4 (58.8 mg, 0.05 mmol) were mixed in 1,4-dioxane (10 mL) and H2O (2.0 mL) in a round-bottom flask. The mixture was heated at 100 °C for 12 h and then partitioned between H2O and EtOAc. The insoluble solid was filtered, and the organic layer was concentrated in vacuo and purified through column chromatography to afford the desired product 23 (170 mg, 91%): mp 153−155 °C; IR (neat) ν 3361, 2979, 1724, 1514, 1233, 1157, 852, 750 cm−1; 1 H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.9 Hz, 2H), 7.35 (s, 1H), 7.10 (s, 1H), 6.96 (s, 1H), 6.54 (s, 1H), 2.95 (t, J = 8.1, 2H), 2.73 (t, J = 8.1, 2H), 1.53 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 152.7, 147.8, 146.5, 138.4, 136.5, 134.7, 129.1, 128.2, 127.8, 125.4, 124.0, 117.5, 116.6, 80.9, 28.5, 28.3, 26.1; HRMS-ESI calcd for C21H22O4N2Na 389.1471, found 389.1473 [M + Na]+.

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ASSOCIATED CONTENT

S Supporting Information *

1

H and 13C spectra of new compounds 4−8, 11, 12, 15−21, and 23. UV and emission spectra of compounds 20 and 21. Computational details, optimized geometries, excited-state structures, and natural transition orbitals. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS NMR and MS measurements were performed at N-BARD, Hiroshima University. This work was partially supported by a Grant-in-Aid for Science Research on Innovative Areas “Stimuli-responsive Chemical Species” (No. 24109008), “piSpace” (No. 21108516), and No. 19350021 from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and by the Tokuyama Science Foundation. This work was granted access to the HPC resources of CINES and of IDRIS under the allocations 2013-[x2013080649] made by GENCI (Grand Equipement National de Calcul Intensif).

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